Radiobiological Meta-Analysis of the Response of Prostate Cancer to Different Fractionations: Evaluation of the Linear–Quadratic Response at Large Doses and the Effect of Risk and ADT

Abstract

The purpose of this work was to investigate the response of prostate cancer to different radiotherapy schedules, including hypofractionation, to evaluate potential departures from the linear–quadratic (LQ) response, to obtain the best-fitting parameters for low-(LR), intermediate-(IR), and high-risk (HR) prostate cancer and to investigate the effect of ADT on the radiobiological response. We constructed a dataset of the dose–response containing 87 entries/16,536 patients (35/5181 LR, 32/8146 IR, 20/3209 HR), with doses per fraction ranging from 1.8 to 10 Gy. These data were fit to tumour control probability models based on the LQ model, linear–quadratic–linear (LQL) model, and a modification of the LQ (LQmod) model accounting for increasing radiosensitivity at large doses. Fits were performed with the maximum likelihood expectation methodology, and the Akaike information criterion (AIC) was used to compare the models. The AIC showed that the LQ model was superior to the LQL and LQmod models for all risks, except for IR, where the LQL model outperformed the other models. The analysis showed a low α/β for all risks: 2.0 Gy for LR (95% confidence interval: 1.7–2.3), 3.4 Gy for IR (3.0–4.0), and 2.8 Gy for HR (1.4–4.2). The best fits did not show proliferation for LR and showed moderate proliferation for IR/HR. The addition of ADT was consistent with a suppression of proliferation. In conclusion, the LQ model described the response of prostate cancer better than the alternative models. Only for IR, the LQL model outperformed the LQ model, pointing out a possible saturation of radiation damage with increasing dose. This study confirmed a low α/β for all risks.

Radiobiological meta-analysis of the response of prostate cancer to high dose rate brachytherapy

“…In recent years, Stereotactic Body RadioTherapy (SBRT) has become widely used to treat prostate cancer [11], with doses per fraction reaching up to 10 Gy. The response of prostate cancer to hypofractionated SBRT protocols has been recently analyzed [12,13,14]. All three studies reported low α/β ratios, in agreement with values obtained from lower doses per fraction.…”

“…In fact, some evidence of a LQL-like response in the dose-response curves of prostate cancer treated with external radiotherapy was recently discussed in Refs. [13,14].…”

“…For example, the models proposed byKuperman & Lubich [49] or Jeong et al[50].The possibility that the LQ model overestimates the effect on prostate cancer of large doses per fraction has already been discussed in the context of external radiotherapy. Refs [13,14]. found some evidence of a moderation of the LQ predicted effect with increasing doses.…”

Variation of the relative biological effectiveness with fractionation in proton therapy: Analysis of prostate cancer response

“…We analyzed the response of prostate cancer because this cancer is treated with photon and proton therapy, with different fractionations with doses per fraction ranging from < 2 to 10 Gy, and there are many published studies reporting tumor control probability that can be used for the purpose of this work 15 . For conventional radiotherapy (photons), we relied on the data set presented in, 20 while for proton therapy we performed a search in Pubmed to find studies reporting control. Tumor control probability was defined as freedom from biochemical relapse at 5 years post‐treatment, both for photons and protons.…”